Is CIC p.Pro2507fs (c.7517dup) pathogenic?

CIC p.Pro2507fs (c.7517dup) is classified Uncertain significance in CIC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-26). Very rare (popmax 0.00427%, afr); Associated with intellectual developmental disorder, autosomal dominant 45.

What condition is associated with CIC p.Pro2507fs (c.7517dup)?

CIC p.Pro2507fs (c.7517dup) is associated with intellectual developmental disorder, autosomal dominant 45 (ClinVar).

How common is CIC p.Pro2507fs (c.7517dup) in the general population?

CIC p.Pro2507fs (c.7517dup) is very rare (popmax 0.00427%, afr) (gnomAD).

CIC p.Pro2507fs

c.7517dup · rs1158987717 · VCV2444056

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00427%, afr)

Conditions

intellectual developmental disorder, autosomal dominant 45

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen); NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.4	GERP 1.4, phastCons 1
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00427% African / African-American · 1/23,402 alleles

Filtering AF 0.00117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000736%

Overall 0.00251% 9/357,886 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00708%	14,116
Remaining individualsnot grpmax-eligible	0.00688%	14,530
African / African-Americangrpmax	0.00427%	23,402
European (non-Finnish)	0.00269%	37,113

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CIC
Protein: p.Pro2507fs
Coding: c.7517dup
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs1158987717
Type: Duplication
Location: chr19:42295147 (GRCh38)
Structure: AlphaFold pLDDT 75.09

Full CIC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder, autosomal dominant 45 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIC p.Arg688fs Pathogenic ★ same condition
CIC p.Cys397fs Likely pathogenic ★ same condition
CIC p.Gly1425fs Pathogenic ★ same condition
CIC p.Pro368fs Pathogenic ★ same condition
CIC p.Ser2026fs Pathogenic ★ same condition
CIC p.Trp343fs Likely pathogenic ★ same condition
CIC p.Pro2503fs Uncertain significance ★ same condition
CIC p.Pro2507Ser Uncertain significance ★ ⚠ same residue

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cic-p-pro2507fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown